MC# 18-15 - A Phase I-II, First-in-Human Study of A166 in Patients with Locally Advanced/Metastatic Solid Tumors which are Human Epidermal Growth Factor Receptor 2 (HER2)-Positive who did not Respond or Stopped Responding to Approved Therapies and Patients with HER2 Positive (by ISH or NGS) or Low Expressing (by IHC) Solid Tumors who did not Respond or Stopped Responding to Approved Therapies

  • Agent(s): A166
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid, Cholangiocarcinoma
  • Phase(s): I, II
  • Drug Classification(s): Targeted Therapy, Immunotherapy, Monoclonal Antibody
  • Molecular Target(s): ERBB2 (HER2)

Mechanism of Action

A166 employs the anti-HER2 antibody to selectively target the cognate HER2 receptor on the surface of the target cancer cells. Following the internalization of HER2-A166 complex through the endosomal–lysosomal pathway, the dipeptide Val-Cit in the linker is cleaved by lysosomal specific proteases to release potent cytotoxic drug (Duostatin-5) that inhibits microtubule assembly, arrests cell cycle and eventually leads to tumor cell apoptosis.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much A166 can be given with an acceptable level of side effects
  • About the safety and tolerability of A166
  • How much A166 is absorbed into the blood and how fast it is removed
  • How proteins that indicate the status of your disease are affected with use of A166
  • If the body develops proteins that work against A166
Inclusion Criteria
  • Patients must be able to provide documented voluntary informed consent.
  • Male or female patient ≥ 18 years.
  • Histologically documented, incurable, locally advanced or metastatic cancer.
  • Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+ determined by validated IHC or have relevant HER2 point mutations where relevant mutations are defined as any mutation listed in Appendix III provided by Precision Oncology Decision Support (PODS) Team at MD Anderson Cancer Center or any mutation deemed to be relevant by both the investigator and sponsor as determined by a discussion between the investigator and sponsor.
  • Patients should have no available therapy likely to convey clinical benefit.
  • Granulocyte count ≥ 1,500/µL, platelet count ≥ 100,000/µL, and hemoglobin ≥ 9 g/dL.
  • Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
  • Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD) formulas. Note that 24-hour urine collection is not required but is allowed.
  • ECOG Performance Status ≤ 1.
  • Women of childbearing potential and men must agree to use an approved method of birth control (e.g., hormonal, barrier) while receiving study drug, and for at least 7 months after the last dose of study drug. Women are excluded from birth control if they had had tubal ligation or a hysterectomy.
  • Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
     

Phase II

Patients must meet the following criteria for inclusion into the study:

  • Patients must be able to provide documented voluntary informed consent.
  • Male or female patient ≥ 18 years.
  • Histologically documented, incurable, locally advanced or metastatic cancer.
  • Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+ determined by validated IHC or have relevant HER2 point mutations where relevant mutations are defined as any mutation listed in Appendix III provided by Precision Oncology Decision Support (PODS) Team at MD Anderson Cancer Center or any mutation deemed to be relevant by both the investigator and sponsor as determined by a discussion between the investigator and sponsor.
  • Regarding previous therapy:
    • Cohort 1: HER2-positive (IHC2+ with FISH confirmation and IHC3+) breast cancer: patients should have progressed after at least 2 previous HER2-directed regimens in metastatic disease with approved therapies.
    • Cohort 2: HER2-positive (IHC2+ with FISH confirmation and IHC3+) gastric cancer: patients should have progressed after at least 1 previous HER2-directed regimens in metastatic disease with approved therapies.
    • Cohort 3: HER2 low expressing (IHC1+ and IHC 2+ without FISH confirmation) breast cancer: patients should have no available therapy likely to convey clinical benefit.
    • Cohort 4: all cancers other than breast cancer with low HER2 expression (IHC 1+ and IHC 2+ without FISH confirmation) and HER2-positive (IHC2+ with FISH confirmation and IHC3 +) cancers other than breast and gastric cancer: patients should have no available therapy likely to convey clinical benefit.
  • Granulocyte count ≥ 1,500/µL, platelet count ≥ 100,000/µL, and hemoglobin ≥ 9 g/dL.
  • Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
  • Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD) formulas. Note that 24-hour urine collection is not required but is allowed.
  • ECOG Performance Status ≤ 1.
  • Women of childbearing potential and men must agree to use an approved method of birth control (e.g., hormonal, barrier) while receiving study drug, and for at least 7 months after the last dose of study drug. Women are excluded from birth control if they had had tubal ligation or a hysterectomy.
  • Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
Exclusion Criteria

Phase I:

  • Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
  • History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.
  • History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued.
  • Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first infusion of study drug.
  • Require supplemental oxygen for daily activities.
  • Documented Grade ≥ 2 peripheral neuropathy.
  • Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy treatment within 4 weeks of first infusion of study drug.
  • Any experimental therapy within 4 weeks of first infusion of study drug.
  • Any major surgical procedure within 4 weeks of first infusion of study drug.
  • Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti-hepatitis B core protein, and positive antibody to the HBsAg (anti-HBs) are not excluded.
  • Have known prior positive test results for human immunodeficiency virus.
  • Uncontrolled hypertension or diabetes.
  • Pregnancy or lactation.
  • Resting QTc > 470 ms at baseline.
  • LVEF < 45% determined by ECHO or MUGA scan.
  • Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.

Phase II:

  • Any patient who was treated in the Phase I part of this study.
  • Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
  • History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.
  • History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued.
  • Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first infusion of study drug.
  • Require supplemental oxygen for daily activities.
  • Documented Grade ≥ 2 peripheral neuropathy.
  • Patient should not have other malignancy in the last three years with the exemption of non-melanoma, non-metastatic skin cancers, low-grade superficial bladder cancer, carcinoma in-situ and cervical intraepithelial neoplasia.
  • Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
  • Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy treatment within 4 weeks of first infusion of study drug.
  • Any experimental therapy within 4 weeks of first infusion of study drug.
  • Any major surgical procedure within 4 weeks of first infusion of study drug.
  • Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti-hepatitis B core protein, and positive antibody to the HBsAg (anti-HBs) are not excluded.
  • Have known prior positive test results for human immunodeficiency virus.
  • Uncontrolled hypertension or diabetes.
  • Pregnancy or lactation.
  • Resting QTc > 470 ms at baseline.
  • LVEF < 45% determined by ECHO or MUGA scan.
  • Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

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Re: MC# 18-15